Over the past two decades, the promise of accelerated drug development and personalized medicine have brought heighten attention to the field of biomarker. But do you really know what biomarker are, how they are developed, and how they are used?
Here, I'll share over 15 years of experience in the fields of biomarker development and translational research to try to answer some of these questions.

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Sunday, October 30, 2011

The Common Rule: Human Samples, Ethics, and the Future of Biomarker Research

The
Common Rule is the regulation governing research involving human subjects
(subpart A of 45 Code of Federal Regulation part 46). The original Common Rule was adopted in 1991
at a time when research was predominantly conducted at universities, colleges,
and medical institutions, and each study generally took place at only a single
site. The evolution of research involving
human subjects over the past two decades has revealed ambiguities in the
original regulations and has led to questions regarding the effectiveness of
the current regulatory framework to meet the needs of the researchers and
research subjects. On July 22 2011, the
department of Health and Human Services (HHS)
released an Advanced Notice of Proposed Rulemaking (ANPRM) for Revisions of the
Common Rule. This noticed was officially
published in the Federal Register on July 25th 2011 under the title:”Human
Subjects Research Protections: Enhancing Protections for Research Subjects and
Reducing Burden, Delay, and Ambiguity for Investigators“. Over the past 90 days, HHS has sought comment
on seven key issues (link):

Revising
the existing risk-based framework to more accurately calibrate the level
of review to the level of risk.

Using
a single Institutional Review Board review for all domestic sites of
multi-site studies.

Implementing
a systematic approach to the collection and analysis of data on
unanticipated problems and adverse events across all trials to harmonize the
complicated array of definitions and reporting requirements, and to make
the collection of data more efficient.

Extending
federal regulatory protections to apply to all research conducted at U.S.
institutions receiving funding from the Common Rule agencies.

Providing
uniform guidance on federal regulations.

As of
October 26th 2011, the 90-day period for public comment has been
closed.

In the
October 20th 2011 of Nature (link),
Krishanu Saha and J. Benjamin Hurlbut discuss these proposed changes to the
Common Rule in the context of biobanking. The authors argue that the revision
to the regulations does little, or even worsens, the current disconnect between
research subjects and researchers.
Indeed, the proposed changes to the Common Rule encourage the use of
blanket informed consent that in effect, ask donors to authorize all possible future
research unless they opt out of specific research categories (see also previous
post: Enabling
Retrospective Biomarker Studies: Resolving the Conflict between Short and Long
Term Goals). While this evolution of
the informed consent removes the ambiguity associated with the original Common
Rule (which resulted in legal disputes), according to the authors, it poses the
risk of reducing the involvement of the public in sample donation by further
distancing the research subjects from the research performed on their
samples. As a solution, the authors
advocate for a model in which the research subjects are actively involved. For example, disease advocacy groups have
succeeded in mobilizing research subjects by making them active players in the
prioritization of research activities. Companies like PatientsLikeMe and 23andMe
attract research subjects by providing feedback about and control over the research
conducted with volunteer samples.

The
idea of offering dynamic feedback about and control over research activities to
research subjects using for example, interactive web portals seems attractive
at first glance. Research subject could
decide in real-time to opt in or out of certain research activities. Researchers could easily gather supplemental
information about research subjects.
However, under this model, the rules of research subject anonymity
imposed by the Health Insurance Portability and Accountability Act (HIPAA)
would be substantially more difficult to maintain and would require considerably
stronger security measures to prevent accidental and/or malicious identification
of subjects. Also, the possibility of
providing to research subjects feedback about research activities would open
the door to the thorny issue of revealing unverified medical finding to the
subjects. Even if such communication were
to occur via the subject’s physician, the exploratory nature of the research precludes
the use of those findings for medical decision making. Actually, the company 23andMe has been under
increased scrutiny from the FDA Center for Devices and Radiological Health
(CDRH) for providing research-grade genetic information to their customers (see
earlier post: Genetic
biomarker: the power and risk of knowing), even though the company claims
that this information is not for medical decision making.

The
proposed changes the Common Rule provide a welcome clarification of the
regulations governing the collection and use of samples from human
subjects. While one can argue that these
changes are not ideal, it is also true that the original version of the Common
Rule exposed researchers and research subjects to a significant level of
ambiguity. Ultimately, the changes to
the Common Rule are designed serve the greater good for society by facilitating
medical research while preserving the right of research subjects.

Thierry Sornasse for Integrated Biomarker Strategy(The views expressed in this post are my own and are not meant to reflect the opinion of any other party)